The human SH-SY5Y neuroblastoma cell line is a very useful cell model for studying preconditioning-induced gene expression and oxidative stress-induced apoptosis. A non-lethal 2-hour serum deprivation leads to up-regulation of NOS1 and thioredoxin (Trx) resulting in compensatory tolerance against oxidative stress. These preconditioned cells exhibited significant neurite outgrowth and synaptogenesis. The observed anti-oxidative and anti-apoptotic effects of GSNO, l-deprenyl and 17 beta-estradiol were mediated by Trx expression via the activation of NO/cGMP/PKG signaling pathway. Trx inhibited caspase-9 and caspase-3 and up-regulated Bcl-2 leading to antiapoptosis. l-Deprenyl-induced hormesis is mediated by the elevation of NOS1, NO, cGMP, and Trx since all of these responses were blocked by respective specific inhibitors. The transfection of Trx antisense also consistently blocked the cytoprotective effects of GSNO, l-deprenyl and 17beta-estradiol. Both anti-oxidative and anti-apoptotic properties of Trx may contribute to not only preconditioning-induced hormesis but also cytoprotection induced by GSNO, l-deprenyl and estrogen derivatives. Two decades ago we and others were very surprised to found out that l-deprenyl prevents not only 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) but also 1-methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity. It is at odds to general belief that through the inhibition of MAO-B, l-deprenyl prevents the conversion of MPTP to the toxic metabolite MPP+ resulting in protection of dopaminergic neurons in vitro and in vivo. The present new findings suggest that (-)-deprenyl may protect against MPP+-induced neurotoxicity through the induction of survival genes and proteins such as Trx, Bcl-2 and MnSOD. Selegiline-induced Trx expression and associated neuroprotection were concomitantly blocked by the antisense against Trx but not the sense or the antisense mutants in both human SH-SY5Y cells and mouse primary midbrain dopaminergic neuronal cultures. Inhibition of Trx reductase by 1-chloro-2,4-dinitrobenzene ameliorated l-deprenyl?s effect that leads to a very interesting notion of the pivotal role of Trx redox cycling in mediating (-)-deprenyl?s neuroprotective mechanism of action. Moreover, other molecular biological evidence suggests that l-deprenyl may also alter the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in addition to the redox protein Trx in the brain. The Trx-based neuroprotective mechanism of (-)-deprenyl may provide insights for developing new therapeutic strategies such as hormesis and chemical preconditioning procedures targeting the induction of cellular defense genes and proteins.